In humans, intrauterine growth restriction (IUGR) is a leading cause of fetal and neonatal morbidity and mortality. Oxygen, nutrients and growth factors are key elements in fetal growth, and insulin-like growth factor (IGFs) and their binding proteins (IGFBP) are particularly important. IGF- 1 is a fetal growth promoter, and IGFBP-1 inhibits IGF-1 action by sequestering it and regulating its access to tissues. Recent evidence suggests that hypoxia and the IGF system are interrelated. In humans we have shown that IGFBP-1 is elevated in the fetal circulation of pregnancies complicated by IUGR, most of which are associated with uteroplacental insufficiency and fetal hypoxia, and that IGFBP-1 is also elevated in cord blood of hypoxic, normal weight human newborns. In animals, maternal and intrauterine hypoxia correlate with IUGR and elevated fetal IGFBP-1. We have discovered 3 consensus sequences for the hypoxia response element (HRE) in intron 1 of the IGFBP-1 gene and that induction of IGFBP-1 by hypoxia involves the HRE and the transcription factor, hypoxia inducible factor-1 (HIF-1). We have found in vitro that human fetal hepatocytes and explants of human fetal heart and kidney respond to hypoxia by increased IGFBP-1 mRNA expression and protein secretion. In this grant the underlying hypothesis is that hypoxia induces IGFBP-1 which inhibits IGF-1 dependent fetal somatic growth. The specific aims focus on elucidating the effects of hypoxia and IGF-1 on fetal tissues to test the hypothesis that hypoxia induces IGFBP-1 in fetal tissues which inhibits IGF-1-mediated cellular mitosis, and elucidating the sequences and the regulators elements in the IGFBP-1 gene that govern the hypoxia response of IGFBP-1 gene regulation. The role of IGFBP-1 as an inhibitor of IGF-1 action, observations of elevated IGFBP-1 under conditions of hypoxia-related fetal growth restriction, and regulation of IGFBP-1 gene expression by hypoxia all support a role for hypoxia in the pathologic process of IUGR. The studies proposed in this grant are important because they propose to elucidate mechanisms underlying fetal growth restriction involving a major fetal growth factor family in the setting of intrauterine hypoxia. The high incidence of intrauterine and neonatal death and neonatal morbidity, including intracranial bleeding and early and late sequelae of IUGR, underscore the importance of understanding mechanisms underlying IUGR due to uteroplacental insufficiency, so that strategies can be developed to prevent it and therapies developed to treat it.